Compositions and methods of chimeric autoantibody receptor t cells

Abstract

The invention includes compositions comprising at least one chimeric autoantibody receptor (CAAR) specific for an autoantibody, vectors comprising the same, compositions comprising CAAR vectors packaged in viral particles, and recombinant T cells comprising the CAAR. The invention also includes methods of making a genetically modified T cell expressing a CAAR (CAART) wherein the expressed CAAR comprises a desmoglein extracellular domain.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a 35 U.S.C. §371 national phase application from, and claims priority to, International Application No. PCT / US2015 / 028872, filed May 1, 2015, and published under PCT Article 21(2) in English, which claims priority to and benefit of U.S. Provisional Application No. 61 / 987,989, filed May 2, 2014, all of which applications are incorporated herein by reference in their entireties.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under AR057001, awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Autoimmunity is the third most common category of disease in the United States, affecting 8% of the population. There are two basic categories of autoimmune diseases: those predominantly caused by T cells, and those predominantly caused by B cells and the autoantibodies they produce. Pemph...

AI Technical Summary

Benefits of technology

The present invention is about a new method for treating autoimmune diseases by using a chimeric autoantibody receptor (CAAR) that targets specific autoantibodies. The invention includes an isolated nucleic acid sequence that encodes a CAAR, which is a fusion of an autoantigen, a transmembrane domain, and an intracellular signaling domain. The isolated nucleic acid sequence can be introduced into a cell, such as a T cell, to create a genetically modified T cell that expresses the CAAR. The genetically modified T cell can then be used to treat autoimmune diseases, such as pemphigus vulgaris, paraneoplastic pemphigus, and pemphigus foliaceus, by targeting and killing the B cells that produce the autoantibodies. The invention provides a specific and effective way to treat autoimmune diseases and offers a new tool for research and development in the field of immunology.

Problems solved by technology

Because pemphigus is a chronic remitting-relapsing disease, such treatments are associated with multiple side effects, including risk of fatal infection and secondary cancers.

However, greater than 80% of patients will relapse (presumably since the efficacy of CD20+B cell depletion by rituximab is usually incomplete), and serious infections are not uncommon, reported to occur in 7% of autoimmune disease patients treated with rituximab, with fatal infection in 1-2%.

However, therapeutic strategies for the treatment of PV to target only the autoreactive B cells do not currently exist.

Systemic corticosteroids, azathioprine, mycophenolate mofetil and cyclophosphamide are effective in the treatment of PV, but non-specifically inhibit lymphocyte proliferation.

As a result, therapeutic strategies can pose serious side effects related to general immune suppression, including fatal infection and secondary cancers.

Images